Document Type

Dissertation

Date of Degree

2009

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmacology

First Advisor

Yuriy M. Usachev

Abstract

Ca2+-mediated regulation of gene expression plays an important role in neuronal plasticity. NFAT (Nuclear Factor of Activated T-cells) is a Ca2+/calcineurin (CaN)-dependent transcription factor that has been implicated in a number of neuronal functions including axon outgrowth, presynaptic remodeling and neural survival. NFAT is activated by Ca2+/CaN-dependent dephosphorylation, whereas re-phosphorylation by glycogen synthase kinase-3β (GSK3β) and several other protein kinases deactivates NFAT and triggers its export from the nucleus. In addition to electrically-mediated Ca2+ signals, neurotrophins can potently regulate NFAT function in neurons as well. However the mechanisms of NFAT activation by electrical activity and neurotrophins are not completely understood.

In aim 1, I found that electrical stimulation produced a mitochondrial Ca2+ cycling-mediated prolonged [Ca2+]i elevation (plateau), which profoundly affected NFAT activity. The elimination of the [Ca2+]i plateau by blocking mitochondrial Ca2+ uptake or release strongly reduced nuclear import of NFAT. Furthermore, preventing Ca2+ mobilization from mitochondria diminished NFAT-mediated transcription. In aim 2, I found that NGF, a family of neurotrophins, potentiated NFAT-dependent transcription triggered by electrical activity through the TrkA-PI3K-Akt-GSK3β pathway and this effect was mediated primarily by NFATc3. Monitoring NFATc3 movement in DRG neurons in real time showed that NGF slowed the rate of NFATc3 nuclear export, which was mimicked by inhibiting GSK3β, whereas blockade of PI3K prevented this effect. Taken together, I proposed that mitochondrial Ca2+ cycling functions as a novel regulatory mechanism for NFAT activation and NFATc3 serves as an integrator of electrical activity and neurotrophin signaling in the regulation of gene expression in DRG neurons.

Keywords

calcium, DRG, mitochondria, NFAT, NGF

Pages

xii, 131 pages

Bibliography

Includes bibliographical references (pages 116-131).

Comments

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Copyright

Copyright 2009 Man Su Kim

Included in

Pharmacology Commons

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